Overview

Who Is at Risk?

Smoking and drinking alcohol may account for roughly 90% of esophageal squamous cell carcinoma cases in Western countries like the United States.[1] Gastroesophageal reflux/Barrett esophagus is associated with an increased risk of esophageal adenocarcinoma. Other factors that may explain the increased risk of
adenocarcinoma of the esophagus include obesity [2] and the use of medications such as
anticholinergics that can predispose to gastroesophageal reflux disease (GERD) by relaxing the lower esophageal
sphincter.[3]

Squamous Cell Carcinoma of the Esophagus

Factors with adequate evidence of increased risk of squamous cell carcinoma of the esophagus

Cigarette smoking and drinking alcohol

Based on solid evidence, smoking cigarettes and drinking alcohol increases the risk of esophageal squamous cell carcinoma. Smoking and drinking alcohol may account for roughly 90% of esophageal squamous cell carcinomas in Western countries like the United States.[1]

Factors with adequate evidence of decreased risk of squamous cell carcinoma of the esophagus

Avoidance of tobacco and alcohol

Based on solid evidence, avoidance of tobacco and alcohol would decrease the risk of squamous cell carcinoma.[1,4]

Magnitude of Effect: Large positive benefit.

Study Design: Evidence obtained from cohort or case-control studies.

Internal Validity: Fair.

Consistency: Multiple studies.

External Validity: Fair.

Chemoprevention

Aspirin and nonsteroidal anti-inflammatory drug (NSAID) use

Benefits

Based on fair evidence, epidemiologic studies have found that aspirin or NSAID use is associated with decreased
risk of developing or dying from esophageal cancer (odds ratio [OR], 0.57; 95% confidence interval [CI], 0.47–0.71).[5]

Magnitude of Effect: Small positive.

Study Design: Evidence obtained from cohort or case-control studies.

Internal Validity: Fair.

Consistency: Good.

External Validity: Fair.

Harms

Based on solid evidence, harms of NSAID use include upper gastrointestinal bleeding and serious cardiovascular events, such as myocardial infarction, heart failure, hemorrhagic stroke, and renal impairment.

Magnitude of Effect: Increased risk, small magnitude.

Study Design: Evidence obtained from randomized controlled trials.

Internal Validity: Fair.

Consistency: Good.

External Validity: Fair.

Adenocarcinoma of the Esophagus

Factors with adequate evidence of increased risk of adenocarcinoma of the esophagus

Gastroesophageal reflux

Based on fair evidence, an association exists between GERD and adenocarcinoma, particularly if the GERD is long-standing and symptoms are severe.[6,7] In a case-control study from Sweden, the OR for patients with recurrent reflux symptoms was 7.7, while the OR for patients with long-standing and severe symptoms was 43.5 (95% CI, 18.3–103.5).[8] A meta-analysis of 1,128 individuals with esophageal adenocarcinoma from five case-control studies reported statistically significant increases in risk with recurrent heartburn (OR, 4.6; 95% CI, 3.3–6.6), regurgitation (OR, 4.6; 95% CI, 3.4–6.1), or both (OR, 4.8; 95% CI, 3.4–6.8). Daily heartburn and regurgitation was associated with an eightfold increase in risk (OR, 8.0; 95% CI, 4.5–14.0).[7]

It is unknown whether elimination of gastroesophageal reflux by surgical or
medical means will reduce the risk of adenocarcinoma of the esophagus.[8,9]

Magnitude of Effect: Unknown.

Study Design: Case-control studies.

Internal Validity: Fair.

Consistency: Good; multiple studies.

External Validity: Fair.

Interventions with adequate evidence of decreased risk of adenocarcinoma of the esophagus

Aspirin and NSAID use

Benefits

Based on fair evidence, epidemiologic studies have found that aspirin or NSAID use is associated with decreased risk of developing or dying from esophageal cancer (OR, 0.57; 95% CI, 0.47–0.71).[5,10]

Magnitude of Effect: Unknown magnitude.

Study Design: Evidence obtained from cohort or case-control studies.

Internal Validity: Fair.

Consistency: Good.

External Validity: Fair.

Harms

Based on solid evidence, harms of NSAID use include upper gastrointestinal bleeding and serious cardiovascular events, such as myocardial infarction, heart failure, hemorrhagic stroke, and renal impairment.

Magnitude of Effect: Increased risk; small magnitude.

Study Design: Evidence obtained from randomized controlled trials.

Internal Validity: Good.

Consistency: Good.

External Validity: Good.

Ablation of Barrett esophagus with dysplasia

Benefits

A randomized controlled trial has found that radiofrequency ablation of Barrett esophagus with severe dysplasia may lead to eradication of both dysplasia and intestinal metaplasia and a reduced risk of disease progression.[11]

Magnitude of Effect: Impact on cancer mortality not known.

Study Design: Evidence obtained from a randomized controlled trial.

Internal Validity: Good.

Consistency: Single study.

External Validity: Good.

Harms

Based on solid evidence, harms of radiofrequency ablation include esophageal stricture and requirement for dilatation and upper gastrointestinal hemorrhage but at low rates. It is possible that overdiagnosis and overtreatment of Barrett esophagus, particularly without severe dysplasia, could lead to a substantial number of harms.

Magnitude of Effect: The low rates of esophageal stricture and requirement for dilatation and upper gastrointestinal hemorrhage may be an understatement of the risks if this practice is widely adopted by less-experienced physicians.

Study Design: Evidence obtained from a randomized controlled trial.

Internal Validity: Good.

Consistency: Single study.

External Validity: Patients representative of a subset of people with dysplasia, particularly severe dysplasia; physicians may not be representative of practicing physicians because this is a new technology and requires specialized knowledge.

Description of the Evidence

Background

Two histological types account for most malignant esophageal
neoplasms: adenocarcinoma and squamous cell carcinoma. The epidemiology of
these types varies markedly. In the 1960s, squamous cell carcinomas comprised
over 90% of all esophageal tumors. The incidence of esophageal adenocarcinomas
has risen markedly for the past 2 decades; it is now more prevalent
than squamous cell carcinomas in the United States and Western Europe, with most
tumors located in the distal esophagus.[1]

Incidence and Mortality

In 2017, it is estimated that 16,940 Americans will be diagnosed with esophageal
cancer and 15,690 will die of this malignancy. Of the new cases, it is estimated that 13,360 will
occur in men and 3,580 will occur in women.[2] Incidence rates generally increase with age in all racial/ethnic groups. In
black men, however, the incidence rate for those aged 55 to 69 years
is close to that of whites aged 70 years and older. In black women, aged
55 to 69 years, the incidence rate is slightly higher than that of white women
aged 70 years and older.[3]

Although the overall incidence of
squamous cell carcinoma of the esophagus is declining, this histologic type
remains six times more likely to occur in black males than in white males.[4] In contrast, the incidence of adenocarcinoma of the esophagus rapidly increased from the 1970s to the mid-1990s.[5]

Male gender is an important predictor of adenocarcinoma of the esophagus. The attributable risk is low enough in women that, although the risk from gender is not modifiable, other risk factors necessarily have limited impact.[5]

Squamous Cell Carcinoma of the Esophagus

Factors with adequate evidence of increased risk of squamous cell carcinoma of the esophagus

Smoking cigarettes and drinking alcohol

In the United States, squamous cell carcinoma of the esophagus is strongly associated with tobacco and alcohol abuse. The relative risk associated with tobacco use is 2.4, and the population attributable risk is 54.2% (95% confidence interval [CI], 3.0–76.2).[6,7] Retrospective cohort studies adjusted for tobacco use have shown a twofold to sevenfold increase in risk of esophageal cancer in alcoholics compared with rates for the general population.[6] Case-control studies have also suggested a significantly increased risk of cancer of the esophagus associated with alcohol abuse.

In China, where the overall prevalence of esophageal carcinoma is much higher than in the United States, esophageal cancer is associated with deficiencies of nutrients, such as retinol, riboflavin, alpha-carotene, beta-carotene, alpha-tocopherol, ascorbate and zinc, and with exposure to specific carcinogens (e.g., N-nitroso compounds).[6]

Factors with adequate evidence of decreased risk of squamous cell carcinoma of the esophagus

Chemoprevention

A prospective, placebo-controlled, esophagus chemoprevention study randomly assigned
610 high-risk Chinese patients.[9] Patients were aged 35 to 64 years
and received either placebo or combined low-dose retinol (15 mg or 50,000 IU)
plus riboflavin (200 mg) and zinc gluconate (50 mg) for 13.5 months. Standard
histological evaluations (including two endoscopic biopsies) were conducted for 93% of
all entered patients. Micronuclei from esophageal cells were obtained before
therapy began and after the 13.5 months of treatment. Serum levels of vitamin
A, beta-carotene, riboflavin, and zinc were obtained at 0, 2, and 13.5 months.

The second report of this study presented micronuclei frequency results.[10] A
statistically significant reduction in the mean percentage of
micronucleated esophageal cells occurred in the active-treatment group compared with the
placebo group. The pattern of cell proliferation, another potential
intermediate endpoint marker, also improved.[11]

Aspirin and nonsteroidal anti-inflammatory drug (NSAID) use

A systematic review and meta-analysis of the association between aspirin and NSAID use and esophageal cancer identified two cohort and seven case-control studies published between 1980 and 2001.[12] Pooled results showed a protective association between aspirin/NSAID use and esophageal cancer (odds ratio [OR], 0.57; 95% CI, 0.47–0.71). The association with aspirin use was statistically significant (OR, 0.50; 95% CI, 0.38–0.66); the association with NSAIDs was borderline significant (OR, 0.75; 95% CI, 0.54–1.0). Aspirin/NSAID use was associated with lower risk of both adenocarcinoma (OR, 0.67; 95% CI, 0.51–0.87) and squamous cell carcinoma (OR, 0.58; 95% CI, 0.43–0.78).[12]

Adenocarcinoma of the Esophagus

Factors associated with increased risk of adenocarcinoma of the esophagus

Gastroesophageal reflux disease (GERD)

The most important epidemiological difference between
squamous cell carcinoma and adenocarcinoma is the strong association
between GERD and adenocarcinoma. The results
of a population-based case-controlled study suggest that symptomatic
gastroesophageal reflux is a risk factor for adenocarcinoma of the esophagus. The
frequency, severity, and duration of reflux symptoms were positively associated
with increased risk of adenocarcinoma of the esophagus.[13] In a case-control study from Sweden, the OR was 7.7 for patients with recurrent reflux symptoms, while the OR for patients with long-standing and severe symptoms was 43.5 (95% CI, 18.3–103.5).[13] A meta-analysis of 1,128 individuals with esophageal adenocarcinoma from five case-control studies reported statistically significant increases in risk with recurrent heartburn (OR, 4.6; 95% CI, 3.3–6.6), regurgitation (OR, 4.6; 95% CI, 3.4–6.1), or both (OR, 4.8; 95% CI, 3.4–6.8). Daily heartburn and regurgitation was associated with an eightfold increase in risk (OR, 8.0; 95% CI, 4.5–14.0).[14] The probable mechanism is that long-standing GERD is associated with the development of Barrett esophagus, a condition in which an abnormal intestinal-type epithelium replaces the stratified squamous epithelium that normally lines the distal esophagus; Barrett esophagus is considered a precursor of esophageal adenocarcinoma.[15] The intestinal-type epithelium of Barrett
esophagus has a characteristic endoscopic appearance that differs from squamous
epithelium.[16] Dysplasia in Barrett epithelium represents a neoplastic
alteration of the columnar epithelium that may progress to invasive
adenocarcinoma.[17]

A population-based cohort study in Sweden shows that patients with Barrett esophagus develop adenocarcinoma of the esophagus at about 1.2 cases per 1,000 person-years of follow-up monitoring, which is about 11.3 times higher than in the general population. Thus, while the relative risk may be elevated, the absolute risk is still not high. Furthermore, over half of the cases of adenocarcinoma of the esophagus are not associated with GERD symptoms.

Interventions with adequate evidence of decreased risk of adenocarcinoma of the esophagus

Aspirin and NSAID use

A systematic review and meta-analysis of the association between aspirin and NSAID use and esophageal cancer identified two cohort and seven case-control studies published between 1980 and 2001.[12] Pooled results show a protective association between aspirin/NSAID use and esophageal cancer (OR, 0.57; 95% CI, 0.47–0.71). The association with aspirin use was statistically significant (OR, 0.50; 95% CI, 0.38–0.66); the association with NSAIDs was borderline significant (OR, 0.75; 95% CI, 0.54–1.0). Aspirin/NSAID use was associated with lower risk of both adenocarcinoma (OR, 0.67; 95% CI, 0.51–0.87) and squamous cell carcinoma (OR, 0.58; 95% CI, 0.43–0.78).[12]

Radiofrequency ablation in dysplastic Barrett esophagus

A randomized controlled trial [18] assessed whether radiofrequency ablation (vs. sham ablation) could eradicate dysplastic Barrett esophagus and decrease the rate of neoplastic progression in patients with Barrett esophagus and dysplasia. Among patients with low-grade dysplasia, eradication of dysplasia occurred in 90.5% of the treatment group compared with 22.7% in the control group; in the high-grade dysplasia group, rates were 81.0% in the treatment group compared with 19.0% in the control group. Additionally, 77.4% of patients in the ablation group had complete eradication of intestinal metaplasia, compared with 2.3% in the control group. Patients in the ablation group had less disease progression, and although cancer was not a primary outcome because expected numbers were small, there were fewer cancers in the ablation group (1.2% vs. 9.3%; P = .045). The complication rate was relatively low; among 84 treated patients, there was one upper gastrointestinal hemorrhage and five strictures that were easily treated.[18]

This study suggests that the treatment of patients with Barrett esophagus and dysplasia may ablate Barrett esophagus and prevent disease progression, but the study provides only weak evidence about whether treatment reduces the outcome of esophageal cancer (because it was not designed to answer that question). Evidence from the study suggests that ablation does not simply coagulate and hide dangerous cells under the surface of the esophagus (those cells could later evolve to cancer). A question entirely separate from this study is whether patients should be screened for Barrett esophagus (this study focused on treatment of patients with Barrett who had been identified as having dysplasia). Furthermore, the study does not discuss the net benefits and harms of an overall program of screening (e.g., of screening patients with GERD or certain GERD symptoms) and the surveillance of patients with Barrett esophagus. The potential for overdiagnosis and overtreatment may be considerable if physicians used results of this study to treat patients with Barrett esophagus and no dysplasia.

About This PDQ Summary

Purpose of This Summary

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about esophageal cancer prevention. It is intended as a resource to inform and assist clinicians who care for cancer patients. It does not provide formal guidelines or recommendations for making health care decisions.

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Updated: March
17, 2017

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